A variety of Clostridium sp. strains which secrete toxins having neurotoxic effects have been discovered since the 1890s up to the present time, and the characterization of toxins that are secreted from these strains has been made during the past 70 years (Schant, E. J. et al., Microbiol. Rev., 56:80, 1992). Among these toxins, botulinum toxin is classified into seven subtypes (subtypes A to G) according to their serological characteristics, and inhibits the exocytosis of acetylcholine at the cholinergic presynapse of a neuromuscular junction in animals having neurological function to thereby cause asthenia universalis. It is known that subtypes B, D, F and G of botulinum toxin cleave synaptobrevin at a specific site, subtypes A and E cleave SNAP25 at a specific site, and subtype C cleaves syntaxin at a specific site (Binz, T. et al., J. Biol. Chem., 265:9153, 1994). Thus, efforts have recently been made to use the neurotoxicity of botulinum toxin for cosmetic or therapeutic purposes. Technologies for using botulinum toxin for treatment of optic diseases (U.S. Pat. No. 6,265,379), pain (U.S. Pat. No. 6,113,915), various autonomic nerve disorders, including sweat gland disorders (U.S. Pat. No. 5,766,605), migraine headache (U.S. Pat. No. 5,714,468), post-operative pain and visceral pain (U.S. Pat. No. 6,464,986), psoriasis and dermatitis (U.S. Pat. No. 5,670,484), various cancers (U.S. Pat. Nos. 6,139,845 and 6,063,768), and neurogenic inflammation (U.S. Pat. No. 6,063,768), have been proposed or attempted.
However, botulinum toxin is the most lethal substance among known biological toxins, with an estimated human median lethal dose (LD50) of 1.3-2.1 ng/kg intravenously or intramuscularly, and 10-13 ng/kg when inhaled. As described above, botulinum toxin has great therapeutic effects on various diseases, but is lethal even in a very small amount due to its strong toxicity. For this reason, when botulinum toxin is to be used in a living body, it is necessary to precisely control the concentration of botulinum toxin.
Meanwhile, microstructures include microneedles, microblades, microknifes, microfibers, microspikes, microprobes, microbarbs, microarrays or microelectrodes, and among them, the term “microneedle” means a technology that forms a hole through the skin by use of a fine needle to increase drug penetration. In particular, when microneedles are used to deliver botulinum toxin, the toxin is injected with several tens to hundreds of microneedles, and thus pain caused by the injection can be alleviated and side effects resulting from a failure to accurately administer the toxin to a desired position can be avoided.
Thus, in this case, there is an advantage in that the drug release rate can be controlled depending on the choice of the material and a preparation method for the microneedle. When the microstructures of the present invention are used to administer botulinum toxin, pain can be alleviated and trace amounts of the toxin can be accurately administered to a desired position. Thus, the microstructures of the present invention are expected to greatly contribute to the safe and convenient medical use of botulinum toxin.